the poliopipeline Research underpins new roadmap to a polio-free world Programmatic benefits of bivalent OPV - from bench to bush!

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1 Summer 2010 Issue 6 Inside this Issue 1 Programmatic benefits of bivalent OPV 2 Identifying and filling epidemiological gaps 3 The importance of optimizing outbreak response 4 Pre-empting outbreaks the poliopipeline A quarterly update of ongoing research in the Global Polio Eradication Initiative Research underpins new roadmap to a polio-free world In 2008, alarmed that polio remained entrenched in the four countries which had never stopped transmission of wild poliovirus, the World Health Assembly (WHA) called for the development of a new strategy to complete polio eradication. Since then, the Global Polio Eradication Initiative (GPEI) introduced a major programme of work to help develop new approaches to interrupt the remaining chains of wild poliovirus transmission. Underpinning the finalization of this new Strategic Plan has been an accelerated research agenda to develop and evaluate new tools and approaches that directly tackle the remaining barriers to eradication in the lingering polio endemic areas, that facilitate a swifter, more thorough outbreak response, and that limits renewed international spread of polio. The accelerated research agenda has focused on a vast array of cross-cutting and country-specific studies. The gamechanging bivalent oral polio vaccine (OPV) was evaluated and developed in record time; the Short Interval Additional Dose (SIAD) strategy was introduced in conflict-affected and outbreak settings; social research was conducted to tailor social mobilization strategies in India, Nigeria and Pakistan; trials were held to more clearly assess vaccine efficacy in multiple settings; seroconversion studies focused on validating supplementary immunization activity (SIA) performance in key reservoir areas; and, mathematical modelling and case-control studies were employed to more clearly highlight areas at particular risk of outbreaks following re-infection. New methods to monitor SIA operations were pioneered to help guide mid-course corrections and new strategies were examined to further boost the efficacy of OPVs and close susceptibility gaps in targeted communities. Finally, supplemental surveillance strategies - including expanding environmental surveillance to key urban reservoir areas - were explored. All of these new approaches, the implementation of which has already had a significant epidemiological impact, particularly in the traditional reservoir areas of northern India and northern Nigeria, have now been institutionalized in the published GPEI Strategic Plan , which was endorsed by the WHA in May. Mr Bill Gates, co-chair of the Bill and Melinda Gates Foundation, told the United States Congress in March 2010 that this new Plan will strike at the final reservoirs of polio and consign this terrible virus to history. There has never been a better opportunity to achieve a polio-free world, as the GPEI is now armed with the required insight and knowledge to tackle the remaining challenges. Due to the fact research will play a key role in both monitoring the implementation of the new strategy and in further sensitizing the approaches, this issue of Polio Pipeline examines in greater depth the role research has played in developing this new strategy, and how it will contribute to its implementation. Programmatic benefits of bivalent OPV - from bench to bush! F ollowing the development and wide utilisation of monovalent oral polio vaccines (OPV) since 2005, transmission of indigenous wild poliovirus type 1 (WPV1) and wild poliovirus type 3 (WPV3) has been restricted to geographically limited areas of four endemic countries: Nigeria, India, Pakistan, and Afghanistan. However, given the ongoing cocirculation of WPV1 and WPV3 in these areas, in November 2007, the Advisory Committee on Poliomyelitis Eradication (ACPE) recommended that the Global Polio Eradication Initiative (GPEI) exploit an opportunity to obtain clinical data on a bivalent OPV (containing type 1 and 3 serotypes) in a clinical trial. In , the clinical trial was conducted in India (in Indore, Pune and Chennai), to compare the rate of seroconversion to each serotype in the bivalent OPV with that of the respective monovalent OPV and trivalent OPV. For both types 1 and 3 polio, bivalent OPV was found to be at least 35% more effective than trivalent OPV and almost as good as the monovalent OPVs. The ACPE reviewed the final trial results in November 2009 and concluded that the strategic use of bivalent OPV in supplementary immunization activities (SIAs) could be an important additional tool in polio eradication, in those areas where both serotypes are circulating. Continued on page 2 Polio Pipeline: to subscribe to this quarterly newsletter, please polioresearch@who.int. 1

2 Table 1 - Utilization of bivalent OPV, by country, during SIAs Cornelia Walther/UNICEF A worldwide premiere: the new bivalent OPV was used for the first time anywhere in December 2009 in Afghanistan, and has since been administered more than 345 million times. Since then, bivalent OPV products from four vaccine manufacturers have been pre-qualified by WHO, while a further two applications for pre-qualification are pending. Between December 2009 and May 2010, over 300 million doses have been procured and utilized in nine countries, with a further rapid scale up of utilization expected throughout 2010 (Table 1). This new vaccine complements the existing arsenal of monovalent and trivalent OPVs, but fills a previously key gap by simultaneously generating immunity to both remaining WPV serotypes. The new bivalent OPV has greatly simplified the logistics of conducting SIAs, and it is anticipated that this tool could greatly accelerate eradication in some settings. The rapid scale-up of the new bivalent OPV is expected to be a cornerstone approach to optimizing SIA strategy during the life of the new GPEI Strategic Plan The field evaluation, development and availability of bivalent OPV further reflects the dynamic nature of the GPEI: evidencebased programming, ongoing learning and tactical adjustments to provide the best possible response to field challenges and Country Date of SIA Number of doses of bivalent OPV used (in millions) Afghanistan 15 December January February March Pakistan 15 February March May Sudan 22 February March India 10 January February April May Nepal 10 April May Benin 24 April Niger 26 March April Nigeria 30 January Grand total 24 April requirements (Figure 1). The very rapid process from field test to actual field application of this vaccine was the result of an extraordinary collaboration between WHO, UNICEF, vaccine manufacturers and national regulatory agencies. Figure 1: From bench to bush : timeline of initial evaluation of bivalent OPV to first-time use Field efficacy study results Jun st licensure 09 Oct 2009 Pre-qualification 29 Oct st field utilisation: Afghanistan, 15 Dec nd field utilisation: India, 10 Jan 2010 Continued on page 3 2

3 Programme evaluation: identifying gaps and providing clear epidemiological picture A s control activities to achieve eradication become more sophisticated by targeting specific poliovirus serotypes with type-specific monovalent oral polio vaccines (OPV) or with the new bivalent OPV containing type 1 and 3 serotypes (particularly where co-circulation of both serotypes exists), there is a concurrent need to better assess the coverage achieved during supplemental immunization activities (SIAs) and to better measure the impact of the SIAs on actual population immunity against polioviruses. As a supplement to existing monitoring procedures, and to help assess vaccination coverage achieved during SIAs, the Global Polio Eradication Initiative (GPEI) adopted the existing methodology of Lot Quality Assurance Sampling (LQAS) to the specific The importance of optimizing outbreak response From case investigation to mass campaigns In April 2010, a wild poliovirus type 1 outbreak was confirmed in Tajikistan, representing the first importation of a wild poliovirus into Europe since the Region was certified polio-free in This outbreak underscores the The importance of a thorough case investigation - setting the stage for an effective response A thorough case investigation will help determine areas and population groups at highest-risk of an outbreak, and will ensure that resources can be targeted in the most effective manner to such areas and groups during the outbreak response. A comprehensive case investigation should be initiated within 48 hours of identification of a suspected outbreak, and consist of: determination if AFP cases display signs/symptoms consistent with polio; active case search for additional AFP cases in the community; needs of the eradication programme. In November 2009, the new cluster LQAS methods were piloted in Nigeria, and applied subsequently over the next six months in Nigeria and other countries in the WHO African Region. To better measure population immunity, a number of seroprevalence surveys have been conducted or are planned for the next six months, both in Asia (ie India and Pakistan) and Africa (ie Nigeria). These seroprevalence surveys usually focus on very young infants, ages 6-11 months, to provide the most conservative population immunity profiles (immunity in these young infants is lowest since maternallyderived antibodies have waned and they have received relatively fewer doses of polio vaccines than older age groups). At end-2009, the GPEI had already risk ongoing indigenous will poliovirus transmission continues to pose to poliofree areas everywhere, and of the need to conduct effective outbreak response activities in the event of an importation. evaluation of routine immunization coverage in the immediate area; collection of travel information of the case(s) and close contacts; and, collection of information on geographical and temporal clustering, age, gender and ethnicity. Further information on polio outbreak response guidelines, including case investigations, are available at: documented a marked increase in type 1 immunity in northern India, from ~80% in 2007 to >99% in 2009, confirming and validating the corresponding decrease in type 1 poliomyelitis cases in this area. While both methods provide important data to validate programmatic efforts to refocus the vaccine mix if necessary, or to provide confidence to programme managers that activities are on the right path, these methods are time- and resource intensive, and should only be used to answer specific important questions. Thus, while both methods are unlikely to become standard tools for the GPEI, these methods will be applied in areas where there are questions about programme performance or where case reporting data may conflict with SIAs coverage data. First and foremost, in any outbreak, an effective initial case investigation must be conducted, to enable the subsequent implementation of comprehensive and effective control measures. Following reports of any case or cluster of cases of acute flaccid paralysis (AFP), an investigation should be launched to determine if the AFP case(s) display signs and symptoms consistent with polio. This will be followed by a virological investigation, ensuring collected specimens are processed in a WHOaccredited laboratory, and prioritizing any isolated poliovirus for intra-typic differentiation and genetic sequencing. If polio is confirmed, surveillance needs to be sensitized through active searches for additional AFP cases in the community, and the state of routine immunization coverage assessed to determine overall population immunity levels. Travel information should be collected to determine whether the case(s) (or their Continued on page 4 3

4 close contacts) had any connections with polio-endemic countries or areas. Finally, the descriptive epidemiology of the case or cluster being investigated should include information on geographical and temporal clustering, and age, gender and ethnicity. Surveillance sensitivity should subsequently further assessed, including laboratory quality indicators (non-polio AFP rates, timeliness of stool collection, processing of stool specimens in a WHOaccredited laboratory, proportion of cases pending, geographical distribution of AFP cases, etc) for the area involved during the previous 12 months, to determine the possibility of transmission that might have previously been missed. Retrospective record reviews should be conducted in health facilities in the area of the outbreak and surrounding areas. Provincial surveillance units across the country should be instructed to notify, by telephone, of the possibility of cases in other provinces. All of these activities will help lay the ground-work for an effective outbreak response. While the response activities are comprehensively conducted on a large-scale, resources and technical support can be prioritized, as appropriate, to those areas and populations identified during the case investigation to be at highest-risk. The outbreak response should follow the international outbreak response guidelines adopted by the World Health Assembly in 2006 (Resolution WHA59.1), with at least three largescale immunization campaigns with the respective monovalent oral polio vaccine. New approaches are now being evaluated to more rapidly and comprehensively build population immunity levels, as part of the outbreak response. The Short Interval Additional Dose (SIAD) approach, to more rapidly boost population immunity levels by administering subsequent doses of monovalent OPV at intervals of two weeks (rather than the traditional interview of four weeks necessary with trivalent OPV), could prove to be an important new tool in outbreak response. This approach has been successfully employed in outbreak settings in the past (eg Kenya, Somalia) and is now being applied in Tajikistan, and to further validate this approach in outbreak settings, a clinical trial in Egypt later in 2010 will assess SIAD in young infants. These activities will provide invaluable insight into optimizing outbreak response, and may potentially lead to a revision of internationally-agreed outbreak response guidelines, if appropriate. In the meantime, to minimise the risk and consequences of an importation, it is critical that all poliofree countries maintain high population immunity levels through high vaccination coverage and strong AFP surveillance. Pre-empting poliovirus: identifying countries at risk of outbreaks R einfection of previously polio-free countries and the resulting outbreak response activities cost the Global Polio Eradication Initiative (GPEI) close to US$1 billion during Those countries most at risk of an outbreak have historically been close to remaining endemic areas or had significant gaps in immunization coverage. However, historical patterns are not always a good indicator for future risk. In , polio cases were reported across Africa in a series of outbreaks on an unprecedented scale 1. Many of these countries experienced their first polio outbreak after stopping indigenous wild poliovirus transmission. To understand the factors that put a country at risk of a polio outbreak a team from the World Health Organization (WHO) and Imperial College London studied polio surveillance and demographic information, including movement data from across Africa. Regression models showed that poor routine immunization coverage with three doses of oral polio vaccine (OPV), high levels of exposure to poliovirus from Nigeria through population movement and a young population were all independently associated with a larger number of polio outbreaks. Periodic supplementary immunization activities were implemented in some countries to protect against outbreaks, but were of variable quality over the period of analysis and no strong protective effect was observed. Country-specific forecasts of outbreak risk six months ahead of time can be produced using routinely reported data on the risk factors that were identified by the regression analysis. These forecasts were found to have a reasonably good predictive ability and identified countries newly at risk in advance of an outbreak, and accurately described the increased number of outbreaks in and show a reduced risk in 2010 as a result of the recent decline in the number of polio cases reported in Nigeria. Continued use of these forecasts will help optimize resource allocation in Africa to minimize the number of polio outbreaks during Resurgence of wild poliovirus types 1 and 3 in 15 African countries, January 2008-March Weekly Epidemiological Record. No. 16, 2009, 84,

5 Call for recruitment Senior Programme Officer - New Vaccines Introduction, Bill and Melinda Gates Foundation Brief job description: The Global Health Delivery group at the Bill and Melinda Gates Foundation is looking for a Senior Programme Officer (SPO) for its New Vaccines Introduction team. The SPO will be primarily responsible for the development and management of product development and launch strategies to ensure fast, broad, and appropriate access to the technologies being developed by the Bill and Melinda Gates Foundation s grantees. Initial focus will be on vaccines for pneumonia and diarrheal diseases. Requirements: The ideal candidate will bring depth and breadth of experience and knowledge in business strategy, project management skills, and product introduction planning for new health technologies, particularly in developing countries. The candidate will have at least 12 years of experience in international public health, global development and/or pharmaceutical and healthcare industries. S/he must either have experience working with global partners such as WHO or GAVI Alliance on global product/vaccine introduction or have strategic planning expertise in marketing and/or product launches. The position is based in Seattle, USA. To view the full job description, please visit Outcomes of the Polio Research Committee (PRC) The fifth meeting of the Polio Research Committee (PRC) was convened at the World Health Organization (WHO) in Geneva, Switzerland in June 2010, to review current research projects, unmet research needs and evaluate new research proposals. The PRC reviewed the current status of the global polio eradication programme and ongoing research projects to support the pre-eradication era (eg outbreak investigation, laboratory methods, costeffectiveness, operational and social research) and post-eradication era (eg antivirals, monoclonal antibody, adjuvant and Sabin IPV development). Assessing the role of IPV in pre- and post-eradication eras A s progress continues towards the interruption of wild poliovirus transmission globally, a substantial programme of work is ongoing to better understand the role inactivated polio vaccine (IPV) could play in both the pre- and post-eradication eras. On 4 June 2010, WHO published 2 new guidance to Member States on the use of polio vaccines (including IPV) and polio immunization in the pre-eradication era. Developed with guidance from the Strategic Advisory Group of Experts on immunization (SAGE) and the SAGE Working Group on IPV, the new WHO Position Paper assists countries with decision-making on polio vaccination schedules and vaccines, given their risk of poliovirus importations and the probable transmission potential for polioviruses in their country. A second publication 3 summarizes the findings of a study that was commissioned The PRC subsequently reviewed more than 20 proposals and endorsed seven new projects (worth a total of US$2.5 million). The new projects include two communication research projects, two seroprevalence studies, a case-control study on mucosal immunity, an alternate seed-strain development project and an intradermal device development project. Now that many research questions are being addressed by existing projects and the priorities are shifting rapidly as polio epidemiology is evolving, the PRC is in the process of updating a list of research priorities, which will be published later in by the Bill and Melinda Gates Foundation in collaboration with WHO to assess the supply landscape and economics of IPVcontaining combination vaccines that would be affordable and appropriate for use in low- and low-middle income countries in the post-eradication era. This study, conducted by the international management consulting firm Oliver Wyman, also identifies and explores the range and feasibility of innovations needed to achieve IPV-containing hexavalent products that could approach the breakeven price for future pentavalent products and stand-alone IPVs in low-income settings. A report 4 by PATH and Working in Tandem Ltd gives an overview of an economic model, which calculated the costs involved in delivering IPV intradermally (ID), including with new delivery methods such as needle-free jet injection or ID adaptors (to control the depth and angle 2 Polio vaccines and polio immunization in the pre-eradiation era: WHO position paper. Weekly Epidemiological Record. No. 23, 2010, 85, The supply landscape and economics of IPV-containing combination vaccines: key findings. Commissioned by the Bill and Melinda Gates Foundation. Prepared by Oliver Wyman, May Available at 4 Improving the affordability of inactivated poliovirus vaccines (IPV) for use in low- and middle-income countries - an economic analysis of strategies to reduce the cost of routine IPV immunization. PATH and Working in Tandem Ltd. April Available at 5

6 About this Newsletter: At the annual meeting of the Advisory Committee on Poliomyelitis Eradication (ACPE) in November 2007, dozens of ongoing or pending research trials and multiple potential new products were discussed. Many of these studies were being managed by the Research and Product Development team at WHO, but a large number of important studies in the overall strategy of GPEI research are being conducted in conjunction with partner organizations such as the US Centers for Disease Control and Prevention (CDC) and UNICEF, as well as collaborators in industry and academics. This increased complexity has made it difficult for the global polio eradication scientific community to remain apprised of the overall research strategy and the ongoing projects within the research agenda. For this reason the ACPE recommended that WHO develop a GPEI research newsletter for the scientific community. This will be integrated with broader inclusion on World Health Organization 2010 All rights reserved. Publications of the World Health Organization can be obtained from Marketing and Dissemination, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: ; fax: ; bookorders@who.int). Requests for permission to reproduce or translate WHO publications whether for sale or for noncommercial distribution should be addressed to Publications, at the above address (fax: ; permissions@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The World Health Organization does not warrant that the information contained in this publication is complete and correct and shall not be liable for any damages incurred as a result of its use. Design & Layout: of the ID injection), at reduced volumes of vaccine per dose; use of adjuvants to allow a reduced antigen content per dose; and, reduced number of doses per IPV immunization schedule. The report suggests such delivery methods could result in per-dose savings of 71-83% compared with the current, standard IPV dose delivered intramuscularly using a needle and syringe. The report concludes that as there are still substantial Available and upcoming publications Fractional Doses of Inactivated Poliovirus Vaccine in Oman. Mohammed AJ, et al. N Engl J Med 2010;362: Implications of a Circulating Vaccine-Derived Poliovirus in Nigeria. Jenkins HE, et al. N Engl J Med 2010;362: Randomized Controlled Clinical Trial of Fractional Doses of Inactivated Poliovirus Vaccine Administered Intradermally by Needle-free Device in Cuba. Resik S, et al. The Journal of Infectious Diseases 2010: 201(9): Polio vaccines and polio immunization in the pre-eradiation era: WHO position paper. Weekly Epidemiological Record. No. 23, 2010, 85, Meeting of the Strategic Advisory Group of Experts on immunization, April conclusions and recommendations. Weekly Epidemiological Record. No. 22, 2010, 85, Poliomyelitis in Tajikistan: first importation since Europe certified polio-free. Weekly Epidemiological Record. No. 18, 2010, 85, Progress towards eradicating poliomyelitis in Afghanistan and Pakistan, Weekly Epidemiological Record. No. 11, 2010, 85, The supply landscape and economics of IPV-containing combination vaccines: key findings. Commissioned by the Bill and Melinda Gates Foundation. Prepared by Oliver Wyman, May Available at Improving the affordability of inactivated poliovirus vaccines (IPV) for use in low- and middle-income countries - an economic analysis of strategies to reduce the cost of routine IPV immunization. PATH and Working in Tandem Ltd. April Available at Meeting of the Strategic Advisory Group of Experts on immunization, April conclusions and recommendations. Weekly Epidemiological Record. No. 22, 2010, 85, Upcoming events development risks with each approach, all three strategy options should be pursued given the potential cost savings which could be achieved. The insights and conclusions from these and other studies and assessments will help further elucidate polio immunization policy. For more information, please see section 6 (Post-wild poliovirus eradication planning) of the new GPEI Strategic Plan June 28: Regional Certification Commission (RCC) for the WHO European Region. Copenhagen, Denmark. July: India Expert Advisory Group on Polio Eradication (IEAG). India. July 28-29: Chad Technical Advisory Group (TAG). N Djamena, Chad. September 22-24: 16 th Informal Consultation of the Global Polio Laboratory Network. Geneva, Switzerland. 6